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Molecular markers in circulating tumour cells from metastatic colorectal cancer patients.

Gazzaniga P, Gradilone A, Petracca A, Nicolazzo C, Raimondi C, Iacovelli R, Naso G, Cortesi E - J. Cell. Mol. Med. (2010)

Bottom Line: CTCs were isolated from peripheral blood and analysed for the expression of aldheyde dehydrogenase 1 (ALDH1), CD44, CD133 (used as markers of stemness), multidrug resistance related protein 5 (MRP5 used as marker of resistance to 5-FU and L-OHP) and survivin (used as a marker of apoptosis resistance).CTCs were found in 27/40 (67%) patients.No correlation was found between the expression of either CD44 and CD133 in CTCs and the outcome of patients, while a statistically significant shorter progression-free survival was found in patients with CTCs positive for the expression of ALDH1, survivin and MRP5.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine, Sapienza University of Rome, Italy. paola.gazzaniga@uniroma1.it

ABSTRACT
The prognosis of metastatic cancer patients is still largely affected by treatment failure, mainly due to drug resistance. The hypothesis that chemotherapy might miss circulating tumour cells (CTCs) and particularly a subpopulation of more aggressive, stem-like CTCs, characterized by multidrug resistance, has been recently raised. We investigated the prognostic value of drug resistance and stemness markers in CTCs from metastatic colorectal cancer patients treated with oxaliplatin (L-OHP) and 5-fluoruracil (5-FU) based regimens. Forty patients with metastatic colorectal cancer were enrolled. CTCs were isolated from peripheral blood and analysed for the expression of aldheyde dehydrogenase 1 (ALDH1), CD44, CD133 (used as markers of stemness), multidrug resistance related protein 5 (MRP5 used as marker of resistance to 5-FU and L-OHP) and survivin (used as a marker of apoptosis resistance). CTCs were found in 27/40 (67%) patients. No correlation was found between the expression of either CD44 and CD133 in CTCs and the outcome of patients, while a statistically significant shorter progression-free survival was found in patients with CTCs positive for the expression of ALDH1, survivin and MRP5. These results support the idea that isolating survivin and MRP5+ CTCs may help in the selection of metastatic colorectal cancer patients resistant to standard 5-FU and L-OHP based chemotherapy, for which alternative regimens may be appropriate.

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Kaplan–Meier curves showing the difference in PFS between patients with CTCs positive and negative for ALDH1 (A), survivin (B) and MRP5 (C) expression.
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fig01: Kaplan–Meier curves showing the difference in PFS between patients with CTCs positive and negative for ALDH1 (A), survivin (B) and MRP5 (C) expression.

Mentions: ALDH1+ CTCs were detected in 9 (33%) out of 27 CTC+ patients. Among these ALDH1+ patients, six had a PD and three a CR. A significant correlation between ALDH1 expression and poor outcome (P∇ 0.046) was found (Fig. 1A). CD44+ and CD133+ CTCs were found in 3/27 (11%) and 2/27 (7%) patients, respectively. No correlation was found between expression of either CD44 and CD133 or outcome of patients (P∇ 0.8 for both). Survivin was detected in CTCs from 13/27 (48%) patients. In the group of survivin positive patients, 10/13 (77%) had PD and 3/13 (23%) had CR. In the group of 14 survivin negative patients, PD was observed in 2/14 (14%) of cases, and CR in 12/14 (86%). The difference in PFS between the two groups was found statistically significant (P < 0.001) (Fig. 1B). MRP5, which transports L-OHP and 5-FU, was found expressed in CTCs from 15/27 patients (55%). Among these patients, 12 were in PD and 3 in CR. MRP5+ patients had a significantly shorter PFS compared to patients whose CTCs were negative for MRP5 expression (P < 0.001) (Fig. 1C). In Fig. 2, RT-PCR amplification products for all genes examined in CTCs from four exemplificative patients are shown. The expression of all markers analysed on CTCs in the population with and without drug resistance is shown in Table 1.


Molecular markers in circulating tumour cells from metastatic colorectal cancer patients.

Gazzaniga P, Gradilone A, Petracca A, Nicolazzo C, Raimondi C, Iacovelli R, Naso G, Cortesi E - J. Cell. Mol. Med. (2010)

Kaplan–Meier curves showing the difference in PFS between patients with CTCs positive and negative for ALDH1 (A), survivin (B) and MRP5 (C) expression.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3822998&req=5

fig01: Kaplan–Meier curves showing the difference in PFS between patients with CTCs positive and negative for ALDH1 (A), survivin (B) and MRP5 (C) expression.
Mentions: ALDH1+ CTCs were detected in 9 (33%) out of 27 CTC+ patients. Among these ALDH1+ patients, six had a PD and three a CR. A significant correlation between ALDH1 expression and poor outcome (P∇ 0.046) was found (Fig. 1A). CD44+ and CD133+ CTCs were found in 3/27 (11%) and 2/27 (7%) patients, respectively. No correlation was found between expression of either CD44 and CD133 or outcome of patients (P∇ 0.8 for both). Survivin was detected in CTCs from 13/27 (48%) patients. In the group of survivin positive patients, 10/13 (77%) had PD and 3/13 (23%) had CR. In the group of 14 survivin negative patients, PD was observed in 2/14 (14%) of cases, and CR in 12/14 (86%). The difference in PFS between the two groups was found statistically significant (P < 0.001) (Fig. 1B). MRP5, which transports L-OHP and 5-FU, was found expressed in CTCs from 15/27 patients (55%). Among these patients, 12 were in PD and 3 in CR. MRP5+ patients had a significantly shorter PFS compared to patients whose CTCs were negative for MRP5 expression (P < 0.001) (Fig. 1C). In Fig. 2, RT-PCR amplification products for all genes examined in CTCs from four exemplificative patients are shown. The expression of all markers analysed on CTCs in the population with and without drug resistance is shown in Table 1.

Bottom Line: CTCs were isolated from peripheral blood and analysed for the expression of aldheyde dehydrogenase 1 (ALDH1), CD44, CD133 (used as markers of stemness), multidrug resistance related protein 5 (MRP5 used as marker of resistance to 5-FU and L-OHP) and survivin (used as a marker of apoptosis resistance).CTCs were found in 27/40 (67%) patients.No correlation was found between the expression of either CD44 and CD133 in CTCs and the outcome of patients, while a statistically significant shorter progression-free survival was found in patients with CTCs positive for the expression of ALDH1, survivin and MRP5.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine, Sapienza University of Rome, Italy. paola.gazzaniga@uniroma1.it

ABSTRACT
The prognosis of metastatic cancer patients is still largely affected by treatment failure, mainly due to drug resistance. The hypothesis that chemotherapy might miss circulating tumour cells (CTCs) and particularly a subpopulation of more aggressive, stem-like CTCs, characterized by multidrug resistance, has been recently raised. We investigated the prognostic value of drug resistance and stemness markers in CTCs from metastatic colorectal cancer patients treated with oxaliplatin (L-OHP) and 5-fluoruracil (5-FU) based regimens. Forty patients with metastatic colorectal cancer were enrolled. CTCs were isolated from peripheral blood and analysed for the expression of aldheyde dehydrogenase 1 (ALDH1), CD44, CD133 (used as markers of stemness), multidrug resistance related protein 5 (MRP5 used as marker of resistance to 5-FU and L-OHP) and survivin (used as a marker of apoptosis resistance). CTCs were found in 27/40 (67%) patients. No correlation was found between the expression of either CD44 and CD133 in CTCs and the outcome of patients, while a statistically significant shorter progression-free survival was found in patients with CTCs positive for the expression of ALDH1, survivin and MRP5. These results support the idea that isolating survivin and MRP5+ CTCs may help in the selection of metastatic colorectal cancer patients resistant to standard 5-FU and L-OHP based chemotherapy, for which alternative regimens may be appropriate.

Show MeSH
Related in: MedlinePlus